Human skin permeation of 3-O-alkyl carbamate prodrugs of naltrexone.

N-Monoalkyl and N,N-dialkyl carbamate prodrugs of naltrexone (NTX), an opioid antagonist, were synthesized and their in vitro permeation across human skin was determined. Relevant physicochemical properties were also determined. Most prodrugs exhibited lower melting points, lower aqueous solubilities, and higher oil solubilities than NTX. The flux values from N-monoalkyl carbamate prodrugs were significantly higher than those from NTX and N,N-dialkyl carbamates. The melting points of N-monoalkyl carbamate prodrugs were quite low compared to the N,N-dialkyl carbamate prodrugs and NTX. Heats of fusion for the N,N-dialkyl carbamate prodrugs were higher than that for NTX. N-Monoalkyl carbamate prodrugs had higher stratum corneum/vehicle partition coefficients than their N,N-dialkyl counterparts. Higher percent prodrug bioconversion to NTX in skin appeared to be related to increased skin flux. N,N-Dialkyl carbamate prodrugs were more stable in buffer and in plasma than N-monoalkyl carbamate prodrugs. In conclusion, N-monoalkyl carbamate prodrugs of NTX improved the systemic delivery of NTX across human skin in vitro. N,N-Dialkyl substitution in the prodrug moiety decreased skin permeation and plasma hydrolysis to the parent drug. The cross-sectional area of the carbamate head group was the major determinant of flux of the N-monoalkyl and N,N-dialkyl carbamate prodrugs of NTX.

Human skin permeation of branched-chain 3-0-alkyl ester and carbonate prodrugs of naltrexone.

PURPOSE: Physicochemical characterization and in vitro human skin diffusion studies of branched-chain ester and carbonate prodrugs of naltrexone (NTX) were compared and contrasted with straight-chain ester and carbonate NTX prodrugs. METHODS: Human skin permeation rates, thermal parameters, solubilities in mineral oil and buffer, and stabilities in buffer and plasma were determined. Partition coefficients between stratum corneum and vehicle were determined for straight- and branched-chain esters with the same number of carbon atoms. RESULTS: Branched prodrugs had lower melting points, lower buffer solubilities, and higher mineral oil solubilities than NTX. The transdermal flux values from all of these branched prodrugs were significantly lower than flux values from the straight-chain ester and the methyl carbonate prodrugs. Straight-chain prodrugs had higher partition coefficient values and higher calculated thermodynamic activities than their branched-chain counterparts. The prodrug hydrolysis to NTX in buffer and plasma was slower for prodrugs with increased branching. CONCLUSIONS: Branched-chain prodrugs with bulky moieties had smaller stratum corneum-vehicle partition coefficients and lower thermodynamic activities that resulted in smaller transdermal flux values than straight-chain prodrugs.

A duplex "Gemini" prodrug of naltrexone for transdermal delivery.

Transdermal naltrexone delivery is desirable in the treatment of narcotic dependence and alcoholism. The purpose of this study was to increase the delivery rate of naltrexone (NTX) across human skin by using a novel prodrug. A duplex "gemini" prodrug of naltrexone was synthesized and evaluated. In vitro human skin permeation rates of naltrexone and prodrug were measured using a flow-through diffusion cell system. Drug concentrations in the skin were quantitated at the end of the diffusion experiment. The prodrug was hydrolyzed on passing through the skin and appeared mainly as naltrexone in the receiver compartment. The prodrug provided a significantly higher naltrexone equivalent flux across human skin in vitro than naltrexone base. The naltrexone equivalent solubilities of naltrexone and the prodrug in the donor solution were not significantly different. No significant increase in drug concentration in the skin after prodrug treatment, as compared to naltrexone, was observed. The naltrexone equivalent permeability from the prodrug exceeded the permeability of naltrexone base by two-fold. Due to the design of this prodrug, toxicities associated with this compound should be nonexistent, because only naltrexone and carbon dioxide (carbonic acid) are released when the prodrug is cleaved.

Left ventricular mural thrombus following myocardial infarction--a follow up study.

Left Ventricular mural thrombus detected by echocardiography in 41 patients after myocardial infarction (MI) were followed up for 4 years. Thirty eight patients were males and mean age of study population was 52.4 years. Echocardiography revealed predominant mural type of thrombi (38 patients) and none showed mobility. All of them showed regional wall motion abnormality (RWMA) and Left Ventricular (LV) aneurysm was found in 28 patients. Embolic events were observed in 6 patients and 1 patient died following embolic stroke. Follow up study revealed persistent left ventricular thrombus in 19 patients and risk factors detected were severe LV dysfunction and LV aneurysm. Six patients had spontaneous resolution and 6 had resolution of the thrombus after anticoagulants. While anticoagulant therapy was very effective in preventing embolism after recent MI (within 3 weeks), it was found not useful in chronic LV thrombi. We observed ongoing embolic risk in chronic LV thrombi with LV aneurysms but a randomised trial is needed to decide the role of anticoagulants in such situation.

Ocular malaria. A clinical and histopathologic study.

PURPOSE: Clinical and histopathologic findings of ocular lesions in malaria rarely have been described. This study reports lesions in three patients with malaria, with a histopathologic study of eyes obtained at autopsy of one of these patients. METHODS: Various ocular lesions were documented in three patients with malarial infection, with histopathologic study of one patient. In all three patients, the diagnosis of malaria was confirmed by the demonstration of malarial parasites in peripheral smears and by fluorescent microscopy of acridine orange-stained buffy coat preparations of venous blood. RESULTS: Multiple superficial blotchy retinal hemorrhages over the posterior pole were seen in the first patient, whereas acute bilateral panuveitis and secondary glaucoma were seen in the second, which on resolution showed multiple blotchy superficial retinal hemorrhages with perivasculitis. The third patient had cerebral malaria and was found to have subconjunctival and retinal hemorrhages. This patient died of pulmonary thromboembolism, and the eyes were obtained at autopsy. On gross examination, there were multiple retinal hemorrhages in the posterior pole. Histopathologic study showed cytoadherence of parasitized erythrocytes as well as schizonts and gametocytes of Plasmodium vivax within the retinal and choroidal blood vessels. CONCLUSION: The authors' findings suggest that patients with unexplained blotchy retinal hemorrhages should be investigated for malarial infection, especially if they reside or have travelled in endemic areas.

Effects of the advent of disease on smoking habit.

PIP: A study was undertaken to determine the effect of the development or disease on patients' smoking habits. Interviews with 841 subjects (591 smokers) were conducted following a standard protocol. Of the 841 subjects, 96 (61 smokers) had hydroceles or hernias and were considered a control group; the remainder had neoplastic diseases, respiratory disorders, diabetes, cardiovascular diseases, psychiatric illnesses, peripheral vascular diseases, and gastrointestinal and liver disorders. Patients with cardiovascular, pulmonary, and neoplastic diseases, diabetes, gastrointestinal diseases, and cirrhosis of the liver significantly reduced or stopped smoking because of medical advice (19%), socioeconomic factors (8%), or aggravation of disease (24%). The advent of disease was associated with an increase in smoking in several patients (including 2 with bronchial asthma and 12 with peripheral vascular disease) because of the apparent belief that smoking is beneficial in overcoming the disease or in controlling pain. Additional long-term studies are needed to explore the relationship between disease and smoking habits.^ieng